Nature structural & molecular biology最新文献_第6页

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control 比较CRISPRi筛选揭示了人类干细胞对mRNA翻译耦合质量控制的依赖

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01616-3

Geraldine Rodschinka, Sergio Forcelloni, Felix M. Kühner, Sascha Wani, Henrick Riemenschneider, Dieter Edbauer, Andrew Behrens, Danny D. Nedialkova

{"title":"Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control","authors":"Geraldine Rodschinka, Sergio Forcelloni, Felix M. Kühner, Sascha Wani, Henrick Riemenschneider, Dieter Edbauer, Andrew Behrens, Danny D. Nedialkova","doi":"10.1038/s41594-025-01616-3","DOIUrl":"https://doi.org/10.1038/s41594-025-01616-3","url":null,"abstract":"The translation of mRNA into proteins in multicellular organisms needs to be carefully tuned to changing proteome demands in development and differentiation, while defects in translation often have a disproportionate impact in distinct cell types. Here we used inducible CRISPR interference screens to compare the essentiality of genes with functions in mRNA translation in human induced pluripotent stem cells (hiPS cells) and hiPS cell-derived neural and cardiac cells. We find that core components of the mRNA translation machinery are broadly essential but the consequences of perturbing translation-coupled quality control factors are cell type dependent. Human stem cells critically depend on pathways that detect and rescue slow or stalled ribosomes and on the E3 ligase ZNF598 to resolve a distinct type of ribosome collision at translation start sites on endogenous mRNAs with highly efficient initiation. Our findings underscore the importance of cell identity for deciphering the molecular mechanisms of translational control in metazoans.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

V-ATPase assembly at leaky lysosomes 漏溶酶体上的v - atp酶组装

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01612-7

Alf Håkon Lystad

引用次数: 0

Neuronal VPS13D loss drives microglial activation 神经元VPS13D缺失驱动小胶质细胞激活

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01623-4

Himanish Basu, Coco Holliday, Isaac M. Chiu

引用次数: 0

A nanobody-based therapeutic targeting Nipah virus limits viral escape 一种基于纳米体的治疗尼帕病毒的方法限制了病毒的逃逸

Nature structural & molecular biology Pub Date : 2025-07-08 DOI: 10.1038/s41594-025-01598-2

Ariel Isaacs, Guillermo Valenzuela Nieto, Xinghai Zhang, Naphak Modhiran, Jennifer Barr, Nazia Thakur, Yu Shang Low, Rhys H. Parry, James B. Barnes, Ronald Jara, Johanna Himelreichs, Yanfeng Yao, Camila Deride, Barbara Barthou-Gatica, Constanza Salinas-Rebolledo, Pamela Ehrenfeld, Jun Jet Hen, Noah Hayes, Devina Paramitha, Mahali S. Morgan, Christopher L. D. McMillan, Martina L. Jones, Trent P. Munro, Alexander A. Khromykh, Patrick C. Reading, Paul R. Young, Keith J. Chappell, Yi Shi, Dalan Bailey, Glenn A. Marsh, Sandra Chiu, Alejandro Rojas-Fernandez, Daniel Watterson

{"title":"A nanobody-based therapeutic targeting Nipah virus limits viral escape","authors":"Ariel Isaacs, Guillermo Valenzuela Nieto, Xinghai Zhang, Naphak Modhiran, Jennifer Barr, Nazia Thakur, Yu Shang Low, Rhys H. Parry, James B. Barnes, Ronald Jara, Johanna Himelreichs, Yanfeng Yao, Camila Deride, Barbara Barthou-Gatica, Constanza Salinas-Rebolledo, Pamela Ehrenfeld, Jun Jet Hen, Noah Hayes, Devina Paramitha, Mahali S. Morgan, Christopher L. D. McMillan, Martina L. Jones, Trent P. Munro, Alexander A. Khromykh, Patrick C. Reading, Paul R. Young, Keith J. Chappell, Yi Shi, Dalan Bailey, Glenn A. Marsh, Sandra Chiu, Alejandro Rojas-Fernandez, Daniel Watterson","doi":"10.1038/s41594-025-01598-2","DOIUrl":"https://doi.org/10.1038/s41594-025-01598-2","url":null,"abstract":"Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic henipaviruses without approved human vaccines or therapies. Here, we report on a highly potent bispecific therapeutic that combines an anti-fusion glycoprotein nanobody with an anti-receptor-binding glycoprotein (RBP) antibody to deliver a dual-targeting biologic that is resistant to viral escape. We show that the nanobody, DS90, engages a unique, conserved site within the fusion glycoprotein of NiV and HeV and provides neutralization and complete protection from NiV disease. Bispecific engineering of DS90 with the anti-RBP monoclonal antibody m102.4 results in neutralization, elimination of viral escape and superior protection from NiV disease compared to leading monovalent approaches. These findings carry implications for the development of cross-neutralizing immunotherapies that limit the emergence of henipaviral escape mutants.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glycerol mediates crosstalk between metabolism and trafficking through the golgin Imh1 甘油通过golgin Imh1介导代谢和运输之间的串扰

Nature structural & molecular biology Pub Date : 2025-07-08 DOI: 10.1038/s41594-025-01600-x

Wan-Yun Chiu, Yi-Hsun Wang, Ming-Chieh Lin, Chun-Chi Lai, Chia-Jung Yu, Fang-Jen S. Lee

引用次数: 0

Returning home: fostering growth of Brazilian research 回国：促进巴西科研的发展

Nature structural & molecular biology Pub Date : 2025-07-03 DOI: 10.1038/s41594-025-01609-2

Sandra M. G. Dias

引用次数: 0

A generalizable multiplexed assay of variant effects for secreted proteins 对分泌蛋白的变异效应的一种可推广的多重分析

Nature structural & molecular biology Pub Date : 2025-06-25 DOI: 10.1038/s41594-025-01583-9

引用次数: 0

Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration 在神经退行性变过程中，小胶质细胞促进炎症细胞死亡

Nature structural & molecular biology Pub Date : 2025-06-25 DOI: 10.1038/s41594-025-01602-9

Guangyan Miao, Tina M. Fortier, Haibo Liu, Dorothy P. Schafer, Katherine A. Fitzgerald, Junhao Mao, Eric H. Baehrecke

{"title":"Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration","authors":"Guangyan Miao, Tina M. Fortier, Haibo Liu, Dorothy P. Schafer, Katherine A. Fitzgerald, Junhao Mao, Eric H. Baehrecke","doi":"10.1038/s41594-025-01602-9","DOIUrl":"https://doi.org/10.1038/s41594-025-01602-9","url":null,"abstract":"The failure to clear dysfunctional mitochondria, cell death and inflammation have been linked in neurodegenerative disease, but their relationship and role in these conditions is not fully understood. Loss of Vps13d prevents clearance of mitochondria, and mutations in human VPS13D have been associated with neurological movement disorders. To investigate the relationship between mitochondrial health, inflammation and neurodegeneration, we created a conditional Vps13d-knockout mouse. Loss of Vps13d in excitatory neurons resulted in behavioral changes and neurodegeneration. Vacuolar protein sorting 13D (VPS13D) deficiency also caused mitochondrial ultrastructural defects and dysfunction in neurons followed by gasdermin E processing, cyclic GMP–AMP synthase (cGAS)–stimulator of interferon response cGAMP interactor (STING) signaling, microglial activation and cell death. Gasdermin E localization with mitochondria in Vps13d-mutant neurons was required for elevated extracellular mitochondrial DNA that promoted activation of microglia. Depletion of microglia suppressed cell death and behavioral phenotypes but not mitochondrial changes in the neuron-specific Vps13d-knockout model, indicating that microglia promote cell death in this model of neurodegenerative disease.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DMXL1 promotes recruitment of V1-ATPase to lysosomes upon TRPML1 activation DMXL1在TRPML1激活时促进v1 - atp酶向溶酶体的募集

Nature structural & molecular biology Pub Date : 2025-06-17 DOI: 10.1038/s41594-025-01581-x

Chan Lee, Matthew J. G. Eldridge, Miguel A. Gonzalez-Lozano, Thomas Bresnahan, Zachary Niday, Donato Del Camino, Tao Fu, Joao A. Paulo, Magdalene M. Moran, Sophie Helaine, J. Wade Harper

{"title":"DMXL1 promotes recruitment of V1-ATPase to lysosomes upon TRPML1 activation","authors":"Chan Lee, Matthew J. G. Eldridge, Miguel A. Gonzalez-Lozano, Thomas Bresnahan, Zachary Niday, Donato Del Camino, Tao Fu, Joao A. Paulo, Magdalene M. Moran, Sophie Helaine, J. Wade Harper","doi":"10.1038/s41594-025-01581-x","DOIUrl":"https://doi.org/10.1038/s41594-025-01581-x","url":null,"abstract":"Lysosomes, central hydrolytic organelles, are regulated by ion flow, including calcium and protons, via transporters and channels to maintain an acidified lumen for hydrolytic activity. TRPML1, a lysosomal ion channel, effluxes cations upon activation, promoting rapid conjugation of ATG8 proteins to the lysosomal membrane in a process known as conjugation of ATG8 to single membranes (CASM). However, our understanding of how TRPML1 activation reorganizes the lysosomal proteome is poorly understood. Here, we identify DMXL1 as a key regulator of lysosomal homeostasis through quantitative proteomics of lysosomes during TRPML1 activation by the agonist MLSA5. DMXL1 is recruited to lysosomes and Salmonella-containing vacuoles, both in a CASM-dependent manner. As the mammalian ortholog of yeast Rav1, DMXL1 assembles with Rav2 ortholog ROGDI and WDR7, and associates with V0 and V1 subunits of the lysosomal V-ATPase. TRPML1 activation drives V1 subunit recruitment to lysosomes in a DMXL1- and DMXL2-dependent manner. DMXL1- and DMXL2-deficient cells display reduced V1-ATPase recruitment, increased lysosomal pH and diminished hydrolytic capacity. Using AlphaFold modeling supported by cross-linking proteomics, we identify interaction interfaces within the DMXL1–ROGDI–WDR7 complex, as well as an ATP6V1A binding interface in DMXL1, whose mutation affects interaction and function. Our findings suggest CASM-dependent DMXL1 recruitment, coupled with V-ATPase assembly, is critical for maintaining lumenal pH and lysosomal function in response to TRPML1 activation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

How protein disorder turns internal dynamics into a long-range regulatory switch 蛋白质紊乱如何将内部动力学转变为远程调节开关

Nature structural & molecular biology Pub Date : 2025-06-16 DOI: 10.1038/s41594-025-01588-4

引用次数: 0